Treating Depression

Depression: Guidelines for Effective Primary Care, Part 2, Treatment

HANI RAOUL KHOUZAM, MD, MPH University of California, San Francisco Dr Khouzam is associate clinical professor of psychiatry at University of California, San Francisco Medical School, Fresno Medical Education Program; clinical instructor in medicine at Harvard Medical School in Boston; and former visiting lecturer in the department of psychiatry and behavioral sciences at the University of Oklahoma College of Medicine in Oklahoma City. He is also staff psychiatrist, medical director, and interim chief of the chemical dependency treatment program in the Veterans Affairs Central California Health Care System in Fresno.

ABSTRACT: Antidepressants and  psychotherapy are effective treatments for major depression. In selecting an antidepressant, consider any previous response or family history of a response to a medication as well as anticipated side effects. Advise patients that antidepressants take at least 4 to 6 weeks to have a full therapeutic effect and that only about half of patients respond to the first drug prescribed. If the patient fails to respond or experiences intolerable side effects, it is usually advisable to substitute an antidepressant with a different mechanism of action. A combined approach using medication and psychotherapy often produces optimal results.

Keywords: depression, antidepressants, psychotherapy

Although most persons with depression can be successfully treated with medications and/or psychotherapy, many do not seek treatment. Left untreated, depression leads to deterioration of interpersonal, social, and vocational functioning, which results in loss of productivity, psychosocial decline, and increased mortality.1,2

Here I outline the treatment options for depression, including complementary therapies. In a previous article (CONSULTANT, July 2007), I discussed diagnosis.


Antidepressant medications and psychotherapy are effective treatments for major depression. Patients who have dysthymic disorder may also benefit from antidepressants.3,4 Those with minor depression (characterized by fewer than 5 depressive symptoms that persist for less than 2 years) may have higher recovery rates with specific treatment (combined medication and psychological intervention) or with supportive care and monitored follow-up appointments.5

If normal bereavement does not resolve, it can lead to major depression. Thus, consider antidepressant therapy for grieving patients whose symptoms of depression last longer than 2 months.6

Treat depression aggressively in patients with comorbid medical conditions. Depression increases patients' sensitivity to existing medical conditions and could lead to poorer self-care, and subsequently worsen the prognosis associated with disorders such as cardiovascular disease, diabetes, and cancer.6 In addition to ameliorating depressive symptoms, appropriate antidepressant therapy improves the patient's overall condition.6,7

Mild cognitive impairment, poor concentration, and psychomotor retardation have been associated with both depression and dementia. A trial of antidepressant treatment is warranted in patients with dementia who also meet the diagnostic criteria for major depression. Older patients with new onset of depression may be at risk for dementia if their depression is not promptly and appropriately treated.6

Other psychiatric disorders frequently coexist with depression. In patients with concurrent anxiety, treat the depression first because such intervention may ameliorate the symptoms of both disorders.8,9 Refer patients with a history of mania, psychosis, or other major psychiatric illness for psychiatric evaluation. Substance abuse, which is common among depressed patients, is not an absolute contraindication to antidepressant treatment.6,10 Appropriate and timely treatment of depression may lead to reduced use of tobacco, alcohol(, and possibly illicit drugs.6,10


Depression varies in severity and duration.11,12 The initiation of a specific treatment depends on the probability of a spontaneous recovery in a 2- to 4-week period. Patients who have moderate to severe symptoms, substantial functional impairment, or a long duration of illness are unlikely to recover and may require immediate psychiatric treatment. Patients with less severe or less persistent symptoms may be appropriate candidates for psychosocial and spiritual interventions with reevaluation in 2 to 4 weeks. The persistence of symptoms after 4 weeks of careful monitoring and psychosocial supportive measures warrants initiation of treatment.3

Patient education. Because mental illness—including depression—is often stigmatized, patients with depression may view themselves as emotionally weak or as having character defects.6 Educate patients about the roles of biological and psychosocial factors, stressful events, and inherited predisposition in causing depression. Help depressed patients understand that their condition results from a combination of biological vulnerability and accumulated psychosocial stressors. Emphasizing the high prevalence of depression may also help decrease the stigma associated with this illness.

Some patients focus on physical symptoms and interpret a diagnosis of depression as a decision to attribute their problems to a mental disorder. Explain that physical symptoms are characteristic of depression. In addition, effective relief of depression often makes chronic illness and physical symptoms more bearable.

Exploring treatment options. In primary care settings, up to 60% of depressed patients respond to initial pharmacological therapy or psychotherapy.11 The choice usually depends on treatment availability and the patient's preference. Although some evidence suggests that pharmacotherapy may be more effective than psychotherapy for the treatment of severe depression, this evidence has not yet been established clearly in primary care settings.13 Combined pharmacotherapy and psychotherapy may be the treatment of choice for patients with recurrent depression and for those whose condition has not responded to either treatment alone.6

Supportive interventions. Primary care providers may not have the luxury of time or the formal training to provide psychotherapy; however, they can initiate interventions to alleviate the symptoms of depression.6 The goals of such interventions are to provide support and to counteract feelings of helplessness and hopelessness. This could be achieved by encouraging patients to schedule relaxing or enjoyable activities every day, and by identifying exaggerated negative or self-critical thoughts. Consider offering brief supportive counseling as initial treatment for patients with mild depression or as an adjunct to pharmacotherapy.14 The objective of supportive interventions is to reduce the effects of depression and to improve general physical and mental health. Resources are listed on page 852.6,15


Although the mechanism of action of antidepressants is not fully understood, all classes of antidepressants can relieve depressive symptoms.6 Table 1 and Table 2 summarize the various classes of antidepressants with their main neurotransmitter actions.3,6,16-21 Antidepressants differ mainly in their side-effect profiles and in their usefulness in treating comorbid conditions, such as generalized anxiety disorder, panic disorder, posttraumatic stress disorder, obsessive-compulsive disorder, and pain syndromes.16,22

Mechanism of action. The earliest antidepressants were monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs).17 These antidepressants affect the neurotransmitter activity of both serotonin (5-HT) and norepinephrine (NE). Their use is based on the theory that depression may be associated with decreased NE and 5-HT neurotransmitter activity; however, because of their side-effect profiles and their need for titration, many primary care providers have been reluctant to prescribe them.6

Other antidepressants were developed that primarily affect a single neurotransmitter system. Selective serotonin reuptake inhibitors (SSRIs) increase only 5-HT neurotransmitter activity and have a better safety and tolerability profiles than MAOIs and TCAs.17 Bupropion increases dopamine (DA) and NE activity but has no effect on 5-HT activity.6

Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine18 and duloxetine,19 have dual actions on both NE and 5-HT. Other antidepressants with different neurotransmitter activities include trazodone, nefazodone, and mirtazapine.6

Side effects. The various classes of antidepressants have different side-effect profiles, although most are associated with sedation, dry mouth, constipation, blurred vision, dizziness, and low blood pressure. Common side effects of SSRIs include difficulty in sleeping, loss of appetite, headache, anxiety, flushing or sweating, and sexual dysfunction. The atypical antidepressants have similar effects but are not associated with sexual dysfunction.3,6

TCAs have a strong tendency to cause sedation, although this effect may lessen with time. In addition to the other effects listed above, TCAs may increase sensitivity to the sun; infrequently, they cause abnormal heart rhythms or seizures in persons with seizure disorders.23

MAOIs can cause low blood pressure, but the main concern with these drugs is the potential for a dangerous interaction with foods that contain tyramine (such as aged cheeses, pickled fish, and red wine). These foods can cause the release of NE from nerve endings. Because MAOIs decrease the metabolism of NE, severe hypertension can result.6

Selecting an antidepressant. More than 80% of depressed patients respond to at least one medication, although individual antidepressants are effective in only 50% to 60% of patients.3 When selecting an antidepres-sant, consider any previous response to that medication, a family history of a response to the same medication, and anticipated side effects. Anxiety and insomnia do not necessarily predict a better response to more sedating medications.20 Although the SSRIs and SNRIs may be more expensive than TCAs, the overall costs of treatment may be equivalent because of the increased frequency of visits to manage the adverse effects of TCAs.21

Newer antidepressants are generally less toxic than TCAs in cases of overdose. However, no particular class of antidepressants is more effective than another in reducing the overall risk of suicide.6

Interactions. Advise patients who are taking antidepressants to consult with you or a pharmacist before adding or discontinuing oth- er prescription or over-the-counter drugs.


Acute treatment. This phase of treatment usually begins with the first dose of antidepressant medication and extends until symptoms remit. In patients who have a good outcome, this phase lasts between 6 and 8 weeks.6

Follow-up. Close follow-up during the first 3 months of treatment is crucial. Nearly half of patients who receive an antidepressant discontinue treatment during the first month.6 A minimum of 3 follow-up appointments during the first 12 weeks of antidepressant treatment may be needed to monitor progress and detect the emergence of side effects. Some clinical guidelines recommend follow-up every 1 to 2 weeks until a substantial improvement in depression occurs.19

Organized follow-up improves outcomes and has been shown to be cost-effective. Follow-up care may include ongoing education, monitoring of medication compliance, and referral for psychiatric consultation if needed. Telephone follow-up may be an alternative for some patients. With the patient's approval, consider en-listing family members to monitor symptoms and to encourage treatment compliance.

Therapeutic response. Advise patients that antidepressants take at least 4 to 6 weeks to have a full therapeutic effect and that only about half of patients respond to the first medication prescribed. Patients who have not responded to a medication or who have had intolerable side effects may be switched either to a different class of antidepressants or to another medication within the same class. Failure to respond to one SSRI does not necessarily predict a lack of response to another one.

Although it is often advisable to switch to an antidepressant with a different mechanism of action, several studies have demonstrated that switching to a second antidepressant within the same class may be helpful in some patients.6 Several studies have demonstrated that dual-action antidepressants tend to be more effective than single neurotransmitter agents.17-21

No washout period is necessary when switching among SSRIs or between an SSRI and a TCA. However, abruptly discontinuing a shorter-acting SSRI (such as citalopram, paroxetine, sertraline, or venlafaxine) may result in a discontinuation-interruption syndrome, which is manifested by the emergence of the initial SSRI side effects, in addition to flu-like symptoms accompanied by tinnitus, vertigo, or paresthesias.

If a trial of a second medication is not beneficial or if the patient's symptoms worsen, psychiatric consultation is recommended.

Continuation treatment. This phase of treatment is necessary to prevent relapse; it should extend at least 6 months beyond the acute phase. During the continuation phase, the same dosage of medication used during the acute phase is maintained. Schedule follow-ups every 3 to 6 months. A return of symptoms indicates the need for adjustment of the dosage, a change of medication, or psychiatric consultation.24

Maintenance. Patients at high risk for relapse (those with 2 or more previous episodes or with major depression that lasts more than 2 years) must continue pharmacotherapy for at least 2 years and possibly indefinitely.24,25

Discontinuation. If you and the patient agree on a trial discontinuation of the medication, withdrawal should be gradual, with tapering over 2 to 3 months, and at least monthly follow-ups, in person or by telephone. If depression recurs, prompt resumption of antidepressant medication should be initiated for at least 3 to 6 months.


Studies have consistently shown that psychotherapy, either alone or in combination with medications, is effective in alleviating depression.26 The therapies studied most often include interpersonal psychotherapy and cognitive-behavioral therapy (CBT). A combined approach using psychotherapy and medication often results in the optimal therapeutic effect. The addition of CBT in patients who have achieved partial remission has been shown to be helpful in improving outcome. Studies have demonstrated that CBT was able to reduce relapses over a 6-year period in depressed patients.26

A referral for psychotherapy does not relieve the referring primary care physician of follow-up obligations, since premature discontinuation of psychotherapy is even more common than premature discontinuation of pharmacotherapy.6 The clinical benefits of psychotherapy should be evident within 6 to 8 weeks.26


St John's wort, S-adenosyl methionine (SAM-e), and omega-3 fatty acid have all been used to treat depression. Advise patients to consult with you before they take an herbal or other supplement.

St John's wort (Hypericum perforatum). This herb is widely used in Europe for the treatment of depression. It is available over-the-counter in many pharmacies and health food stores in the United States. Although it may have some merit in treating mild to moderate depression of limited duration, it is not recommended for major depression.27 It appears to have multiple actions, including inhibition of MAO and inhibition of 5-HT uptake.

Many drugs interact with St John's wort. It can increase the metabolization of some drugs, including oral contraceptives and protease inhibitors, thus reducing their effects. Because it also decreases the effects of cyclosporine, rejection of transplanted organs can occur. St John's wort also increases sensitivity to sunlight. Studies are under way about its place in the armamentarium.

SAM-e. The production of SAM-e is impaired in persons who are depressed.1 It has been hypothesized that supplementation with SAM-e increases levels of 5-HT, DA, and phosphatides, and enhances 5-HT- and DA-receptor site binding, thus leading to amelioration of depression. SAM-e breaks down into homocysteine, elevated levels of which have been correlated with heart disease.28

Omega-3 fatty acid. Although it has been reported to alleviate depression, omega-3 fatty acid may exert a dose-related effect on bleeding time.27 Careful ongoing monitoring of bleeding time may be necessary if this supplement is used to treat depression.


Augmentation and combination therapy. The addition of another agent such as lithium(, thyroid hormone, a stimulant, or another antidepressant may be helpful for a patient with refractory depression.6 Augmentation with an atypical antipsychotic medication may also be useful.29 When major depression has psychotic features, the combination of an antipsychotic with an antidepressant may be an appropriate initial strategy; however, some clinicians prefer to treat the psychosis first before adding an antidepressant.30

Electroconvulsive therapy (ECT). If aggressive pharmacological interventions are not effective, consider ECT. To reduce the cognitive side effects of ECT, various strategies have been used31:

  • Widely spaced treatments, with only one seizure per session.
  • Unilateral nondominant placement of electrodes.
  • Brief-pulse rather than sine-wave stimulus wave forms.
  • Decreased dose of electricity.
  • Tailored doses of anesthetic before treatment.
  • Avoidance of concomitant psychotropic medication.

More recently, repetitive transcranial stimulation and vagal nerve stimulation have been tested and appear to be somewhat effective.32

Surgery. Psychosurgical interventions, including MRI-guided ste- reotactic cingulotomy, have been successful in some treatment-resistant patients.33

Light therapy. Patients with seasonal affective disorder can be treated with exposure to bright light (at least 2500 lux), preferably in the morning. Some patients may also respond to lithium and antidepressants.33

Treatment of medical conditions. Medical complaints that are not adequately addressed worsen depression and complicate treatment. Pain is one of the most frequently reported and bothersome physical symptoms.23 Even in the absence of depression, antidepressants have been shown to play a role in the treatment of pain.

Both 5-HT and NE are important modulators of pain sensations. TCAs with dual mechanisms of action, such as amitriptyline, are effective in controlling chronic pain, whereas SSRIs have more modest effects.23 Dual-action agents, such as venlafaxine, may be more effective in the relief of pain and have fewer adverse effects than TCAs.19 Duloxetine has also been shown to reduce overall pain severity in depressed patients, compared with placebo.20 This reduction in pain occurred more rapidly than the antidepressant effect, which suggests that there may be a different mechanism of action for pain relief.


Depression is often chronic, with alternating relapses and remissions. About one third of patients with a single episode of major depression will have another episode within 1 year after discontinuing treatment, and more than half will have a recurrence during their lifetimes.25 Greater severity of depression, persistence of symptoms, and a higher number of previous episodes are the best predictors of recurrence.6 Chronic depression frequently develops in patients with multiple recurrences and in those with comorbid medical and psychiatric conditions.6


1. Wells KB, Stewart A, Hays RD, et al. The func-tioning and well-being of depressed patients: results from the Medical Outcomes Study. JAMA. 1989;262:914-919.
2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM IV-TR). 4th ed. Washington, DC: American Psych-iatric Association; 2000.
3. Schulberg HC, Katon W, Simon GE, Rush AJ.
Treating major depression in primary care practice: an update of the Agency for Health Care Policy and Research practice guidelines. Arch Gen Psychiatry. 1998;55:1121-1127.
4. Thase ME, Fava M, Halbreich U, et al. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry. 1996;53:777-784.
5. Williams JW, Mulrow CD, Kroenke K, et al. Case-finding for depression in primary care: a randomized trial. Am J Med. 1999;106:36-43.
6. Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med. 2000;343: 1942-1950.
7. Simon GE, Katon W, Rutter C, et al. Impact of improved depression treatment in primary care on daily functioning and disability. Psychol Med. 1998; 28:693-701.
8. Depression Guideline Panel. Depression in Primary Care. Clinical practice guideline, no. 5. Rockville, Md: US Department of Health Services, Agency for Health Care Research and Quality; April. AHRQ publication 93-0551.
9. Gorman JM, Kent JM. SSRIs and SNRIs: broad spectrum of efficacy beyond major depression. J Clin Psychiatry. 1999;60(suppl 4):33-39.
10. Khouzam HR, Field S. Somatization disorder: clinical presentation and treatment in primary care. Hospital Physician. 1999;35(4):20-25.
11. Kendler KS, Gardner CO Jr. Boundaries of major depression: an evaluation of DSM-IV criteria. Am J Psychiatry. 1998;155:172-177.
12. Judd LL, Akiskal HS. Delineating the longitudinal structure of depressive illness: beyond clinical subtypes and duration thresholds. Pharmacopsychiatry. 2000;33:3-7.
13. Miller MC, Paulsen RH. Suicide assessment in the primary care setting. In: Jacobs DG, ed. The Harvard Medical School Guide to Suicide Assessment and Intervention. San Francisco: Jossey-Bass; 1999: 520-539.
14. Brody DS, Thompson TL II, Larson DB, et al. Strategies for counseling depressed patients by primary care physicians. J Gen Intern Med. 1994;9: 569-575.
15. Khouzam HR. Chronic fatigue syndrome: update on diagnosis and treatment. Consultant. 2000;40: 1441-1450.
16. Khouzam HR, Donnelly NJ. Posttraumatic stress disorder. Safe, effective management in the primary care setting. Postgrad Med. 2001;110:60-78.
17. Zajecka JM, Beeler M. Improving long-term adherence to treatment in major depression. In: Alpert JE, Fava M, eds. Handbook of Chronic Depression. New York: Marcel Dekker, Inc; 2004:403-410.
18. Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001; 178:234-241.
19. Detke MJ, Lu Y, Goldstein DJ, et al. Duloxetine, 60 mg once daily, for major depressive disorder: a randomized double-blind placebo-controlled trial. J Clin Psychiatry. 2002;63:308-315.
20. Simon GE, Heiligenstein JH, Grothaus L, et al. Should anxiety and insomnia influence antidepresant selection: a randomized comparison of fluoxetine and imipramine. J Clin Psychiatry. 1998;59:49-55.
21. Simon GE, Heiligenstein J, Revicki D, et al. Long-term outcomes of initial antidepressant drug choice in a "real world" randomized trial. Arch Fam Med. 1999;8:319-325.
22. Khouzam HR. Chronic pain and its management in primary care. South Med J. 2000;93:946-952.
23. Tummala R, Zajecka JM. Tricyclics: still solid performers for the savvy psychiatrist. Curr Psychiatry. 2002;1:1-7.
24. Thase ME. Long-term nature of depression. J Clin Psychiatry. 1999;60(suppl 14):3-9.
25. Zajecka JM. Clinical issues in long-term treatment with antidepressants. J Clin Psychiatry. 2000; 61(suppl 2):20-25.
26. Antonuccio DO, Danton WG, DeNelsky GY. Psychotherapy versus medication for depression: challenging the conventional wisdom with data. Professional Psychology: Research and Practice. 1995;26:574-585.
27. Murray MT. Natural Alternatives to Prozac. New York: Quill; 1996:174-175.
28. S-Adenosyl-l-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease. Summary, Evidence Report/Technology Assessment: Number 64. Rockville, Md: Agency for Healthcare Research and Quality; 2002. AHRQ publication 02-E033.
29. Thase ME. What role do atypical antipsychotic drugs have in treatment-resistant depression? J Clin Psychiatry. 2002;63:95-103.
30. Spiker DG, Perel JM, Hanin I, et al. The pharmacological treatment of delusional depression: part II. J Clin Psychopharmacol. 1986;6:339-342.
31. Task Force Report of the American Psychiatric Association. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training and Privileging. Washington, DC: American Psychiatric Association; 1990:61-62.
32. Berman RM, Narasimhan M, Sanacora G, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47:332-337.
33. Silverstone PH. The mind, brain, body connection: treating people with depression in the 21st century. In: Program and abstracts of the International Congress of Biological Psychiatry; February 9-13, 2004; Sydney, Australia. Symposium 24.
34. FDA Public Health Advisory. Worsening depression and suicidality in patients being treated with antidepressant medications. March 22, 2004.
35.Bridge JA, Iyengar S, Salary CB. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007;297:1683-1696.
36.Bonari L, Bennett H, Einarson A, Koren G. Risks of untreated depression during pregnancy. Can Fam Physician. 2004;50:37-39.
37.Chung TK, Lau TK, Yip AS, et al. Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosom Med. 2001;63:830-834.
38. Austin MP, Mitchell PB. Use of psychotropic medications in breast-feeding women: acute and prophylactic treatment. Aust N Z J Psychiatry. 1998; 2:778-784.
39. Gentile S. Use of contemporary antidepressants during breastfeeding: a proposal for a specific safety index. Drug Saf. 2007;30:107-121.